Degenerative disease of the central nervous system, such as Alzheimer's and Parkinson's disease, are characterized by the accumulation of abnormal protein deposits. Recent studies of patients suffering from Parkinson's disease have clearly suggested that a major effect of mutations in certain genes may result in abnormal processing and accumulation of unwanted proteins. The buildup of damaged proteins under normal conditions is a relatively rare phenomenon; normally, cells can quickly eliminate unwanted and misfolded proteins through an active cellular garbage collection system called the proteasome. In pathological situations such as Parkinson's disease, however, scientific studies have increasingly suggested that this scavenging system is impaired and can lead to an accumulation of intracellular debris that can directly impair cellular function. Increasing our understanding of the cellular mechanisms for disposal of these unwanted proteins and of the effects of noxious protein accumulation in models of Parkinson's disease may allow the development of rational and effective treatment for these disorders. Nevertheless, despite the strong cell-based and pathological evidence that supports the idea that proteasome dysfunction may play a significant part in the development of Parkinson's disease (as well as a variety of similar diseases), up until now there have been no animal models that could allow researchers to directly test the question of whether waste removal by the proteasome plays a crucial role in the progression of neurodegenerataive diseases. Through the funds provided by The Michael J. Fox Foundation, we are working to develop a transgenic mouse that allows us to directly test this question. Under normal circumstances, the transgenic mouse produces a green fluorescent protein that is quickly inhibited; this green fluorescent protein accumulates in cells and serves as a direct measure of the efficiency of the proteasome. By breeding these mice with transgenic pre-clinical models of Parkinson's and Alzheimer's disease, we ultimately hope to directly address the question that abnormal protein accumulation blocks the waste removal system in living animals.